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PD-1/PD-L1 Inhibitors plus Chemotherapy Versus Chemotherapy Alone for Resectable Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

ABSTRACT: Background: The benefit of adding programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors to the treatment of early-stage non-small cell lung cancer (NSCLC), both neoadjuvant therapy (NAT) and adjuvant therapy (AT), is not yet fully elucidated. Methods: We searched PubMed, Embase, and Cochrane databases for randomized controlled trials (RCT) that investigated PD-1/PD-L1 inhibitors plus chemotherapy for resectable stage NSCLC. We computed hazard ratios (HRs) or odds ratios (ORs) for binary endpoints, with 95% confidence intervals (CIs). Results: A total of seven RCTs comprising 3915 patients with resectable stage NSCLC were randomized to chemotherapy with or without PD-1/PD-L1 inhibitors as NAT or AT. As NAT, the PD-1/PD-L1 inhibitors plus chemotherapy group demonstrated significantly improved overall survival (HR 0.66; 95% CI 0.51-0.86) and event-free survival (HR 0.53; 95% CI 0.43-0.67) compared with the chemotherapy alone group. There was a significant increase in favor of the PD-1/PD-L1 inhibitors plus chemotherapy group for major pathological response (OR 6.40; 95% CI 3.86-10.61) and pathological complete response (OR 8.82; 95% CI 4.51-17.26). Meanwhile, as AT, disease-free survival was significant in favor of the PD-1/PD-L1 inhibitors plus chemotherapy group (HR 0.78; 95% CI 0.69-0.90). Conclusions: In this comprehensive systematic review and meta-analysis of RCTs, the incorporation of PD-1/PD-L1 inhibitors alongside chemotherapy offers a promising prospect for reshaping the established treatment paradigms for patients diagnosed with resectable stages of NSCLC. Moreover, our analyses support that neoadjuvant administration with these agents should be encouraged, in light of the fact that it was associated with an increased survival and pathological response, at the expense of a manageable safety profile.

SUBMITTER: Pasqualotto E

PROVIDER: S-EPMC10648147 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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PD-1/PD-L1 Inhibitors plus Chemotherapy Versus Chemotherapy Alone for Resectable Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Pasqualotto Eric E Moraes Francisco Cezar Aquino de FCA Chavez Matheus Pedrotti MP Souza Maria Eduarda Cavalcanti MEC Rodrigues Anna Luíza Soares de Oliveira ALSO Ferreira Rafael Oliva Morgado ROM Lopes Lucca Moreira LM Almeida Artur Menegaz de AM Fernandes Marianne Rodrigues MR Santos Ney Pereira Carneiro Dos NPCD

Cancers 20231026 21

<b>Background:</b> The benefit of adding programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors to the treatment of early-stage non-small cell lung cancer (NSCLC), both neoadjuvant therapy (NAT) and adjuvant therapy (AT), is not yet fully elucidated. <b>Methods:</b> We searched PubMed, Embase, and Cochrane databases for randomized controlled trials (RCT) that investigated PD-1/PD-L1 inhibitors plus chemotherapy for resectable stage NSCLC. We computed hazard ratios (H ...[more]

PMID: 37958317

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Project description:Immune checkpoint inhibitors (ICIs) are recommended as first-line treatment for late-stage non-small cell lung cancer (NSCLC), either as monotherapy or in combination with chemotherapy. However, efficacy and safety comparisons between ICIs as monotherapy and ICIs with chemotherapy are lacking. We searched PubMed, Embase, and Cochrane Library for randomized controlled trials published before February 29th, 2020, with the search terms "immunotherapy" and "chemotherapy". 10 eligible trials were identified with a total of 5,956 patients. Of these patients, 3,204 received immune therapy and 2,752 received chemotherapy. PD-1 inhibitors with chemotherapy improved OS (HR 0.84, 0.77-0.92), PFS (HR 0.80, 0.75-0.85), and objective response rate (ORR) (odds ratio (OR) 2.55, 1.20-5.28) compared to PD-1 inhibitors as monotherapy. In contrast, PD-L1 inhibitors plus chemotherapy showed no significant differences in OS, PFS, or ORR compared with PD-L1 inhibitors as monotherapy. When patients were stratified according to PD-L1 expression level, patients with high PD-L1 expression (≥ 50%) receiving PD-1 inhibitors plus chemotherapy had improved PFS, but not other outcomes, compared to PD-1 inhibitors as monotherapy. In these patients, PD-L1 inhibitors plus chemotherapy showed no significant difference in survival compared with PD-L1 inhibitors. In the low PD-L1 expression group (1%-49%), PD-1 inhibitors plus chemotherapy improved OS and PFS, but no advantage was observed in PD-L1 inhibitors plus chemotherapy in OS, PFS, or ORR compared with PD-L1 inhibitor monotherapy. When comparing PD-1/PD-L1 inhibitors plus chemotherapy with PD-1/PD-L1 inhibitors monotherapy, no significant differences were observed in the rate of immune-related adverse events (AEs). In summary, for treating patients with late-stage NSCLC, PD-1 inhibitors plus chemotherapy have improved efficacy compared with PD-1 inhibitor monotherapy, but PD-L1 inhibitors plus chemotherapy have similar efficacy as PD-L1 monotherapy. Survival benefits of PD-1/PD-L1 inhibitors combined with chemotherapy were particularly significant in patients with low PD-L1 expression levels.Systematic review registrationPROSPERO, identifier CRD42020166678 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=166678).

Project description:BackgroundPembrolizumab plus platinum-based chemotherapy has demonstrated improved clinical outcomes over chemotherapy alone in patients with previously untreated advanced/metastatic non-small cell lung cancer (NSCLC), regardless of tumor programmed death ligand 1 (PD-L1) expression. This study pooled data from 3 randomized controlled trials to evaluate outcomes with pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced/metastatic NSCLC negative for PD-L1 (ie, a tumor proportion score < 1%).MethodsIndividual patient data were pooled from KEYNOTE-021 cohort G (nonsquamous; NCT02039674), KEYNOTE-189 (nonsquamous; NCT02578680 and NCT03950674), and KEYNOTE-407 (squamous; NCT02775435). Treatment comprised pembrolizumab plus chemotherapy (pemetrexed and platinum for nonsquamous histology and carboplatin and paclitaxel/nab-paclitaxel for squamous histology) or chemotherapy alone. Responses were assessed according to Response Evaluation Criteria in Solid Tumors version 1.1 by blinded, independent, central review. No α was assigned to this descriptive, exploratory analysis.ResultsFour hundred forty-four of the 1328 patients (33.4%) who were enrolled across the 3 trials had PD-L1-negative tumors (256 on pembrolizumab plus chemotherapy [nonsquamous, n = 155; squamous, n = 94; other, n = 7] and 188 on chemotherapy alone [nonsquamous, n = 83; squamous, n = 99; other, n = 6]). The median time from randomization to the data cutoff was 28.0 months (range, 14.7-55.4 months). Pembrolizumab plus chemotherapy improved overall survival (OS; hazard ratio [HR], 0.63; 95% CI, 0.50-0.79) and progression-free survival (HR, 0.68; 95% CI, 0.56-0.83) over chemotherapy. Sixteen patients in the pembrolizumab plus chemotherapy arm completed 2 years of treatment; the objective response rate was 87.5% (95% CI, 61.7%-98.4%), and the 3-year OS rate was 100%. Adverse events (AEs) were experienced by 99.2% of the patients who received pembrolizumab plus chemotherapy and by 98.9% of the patients who received chemotherapy alone, with grade 3 or higher AEs occurring in 71.4% and 72.0%, respectively; immune-mediated AEs and infusion reactions were experienced by 29.0% and 12.4%, respectively.ConclusionsPembrolizumab plus chemotherapy demonstrated response and survival improvements with manageable safety in comparison with chemotherapy alone in PD-L1-negative advanced/metastatic NSCLC, and it is a standard-of-care first-line therapy for patients with advanced NSCLC, regardless of PD-L1 expression.Lay summarySome tumors produce a protein called programmed death ligand 1 (PD-L1), which interacts with the body's immune system and prevents an immune response against cancer. Antibody therapies such as pembrolizumab block interactions between tumor PD-L1 and the immune system and enable an immune response. Used alone, pembrolizumab provides benefit for patients with non-small cell lung cancer (NSCLC) tumors that produce PD-L1. However, when it is combined with chemotherapy, which can stimulate anticancer immune responses, pembrolizumab provides a benefit, regardless of tumor PD-L1 production. This article shows that among patients with NSCLC whose tumors produce no PD-L1, outcomes are better with pembrolizumab plus chemotherapy in comparison with chemotherapy alone.

Project description:BackgroundAdvanced triple-negative breast cancer (TNBC) presents significant therapeutic challenges, particularly in Asian populations, which exhibit distinct biological and genetic characteristics. Immunotherapy combined with chemotherapy has emerged as a promising approach; however, its efficacy compared to chemotherapy alone remains under investigation. This meta-analysis aims to evaluate the clinical outcomes of PD-1/PD-L1 inhibitors combined with chemotherapy (PIC) versus chemotherapy alone in the treatment of advanced TNBC in Asian patients.MethodsA systematic literature search was performed across six databases for phase 3 randomized controlled trials (RCTs). Only studies comparing the outcomes of PIC versus chemotherapy alone in patients with advanced TNBC, including subgroup analyses of Asian populations, were included. Data were pooled to assess overall survival (OS), progression-free survival (PFS), responses, and safety profiles.ResultsA total of 1041 patients from five phase 3 RCTs were included in the final analysis. Compared to chemotherapy alone, PIC therapy significantly improved PFS (hazard ratio [HR]: 0.74 [0.62, 0.88], P = 0.0008). No significant difference was observed in OS (HR: 0.78 [0.55, 1.12], P = 0.18), although a slight trend favoring PIC therapy was noted. Among PD-L1-positive patients, both OS (HR: 0.62 [0.44, 0.86], P = 0.005) and PFS (HR: 0.66 [0.50, 0.86], P = 0.003) were significantly improved in the PIC group. The PIC group also exhibited a substantially higher OS rate at 12-36 months and a higher PFS rate at 6-30 months. However, the incidence of immune-related AEs (irAEs) (risk ratio [RR]: 1.69 [1.33, 2.15], P < 0.0001) and grade 3-5 irAEs (RR: 3.11 [1.59, 6.10], P = 0.001) was significantly higher in the PIC group. The most common irAEs in the PIC group were hypothyroidism (14.40%), dermatitis (10.00%), and infusion reactions (8.85%). Both treatment groups exhibited similar response rates and treatment-related AEs (TRAEs).ConclusionsIn Asian patients with advanced TNBC, PIC significantly improved survival compared to chemotherapy alone. Although the combination therapy was associated with a higher incidence of irAEs, its clinical benefits support its use as a viable treatment option for this population.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42024622428.

Project description:BackgroundImmunotherapy has afforded new treatment options for extensive small cell lung cancer (ES-SCLC). However, reports on the effectiveness of immune checkpoint inhibitors (ICIs) combined with chemotherapy on survival in ES-SCLC patients are inconsistent. Therefore, we conducted a meta-analysis on the efficacy and safety of ICI combined with chemotherapy for ES-SCLC.MethodsWe searched for randomized controlled clinical trials related to first-line treatment of ES-SCLC with ICI combined with chemotherapy in PUBMED, ESMO, ASCO, and WCLC since 2018. The primary outcome was overall survival (OS).ResultsFour studies were included. Compared to chemotherapy alone, ICI in combination with chemotherapy as first-line treatment reduced the risk of death (hazard ratio [HR]: 0.76; 95% CI: 0.68-0.86; P < 0.00001) and disease progression (HR: 0.76; 95% CI: 0.68-0.84; P < 0.00001). The objective response rate (ORR) with ICI plus chemotherapy was significantly higher than that with chemotherapy alone (HR: 1.10; 95% CI: 1.02-1.19, P = 0.01). The duration of response (DoR) rate at one year was also better with ICI plus chemotherapy (HR: 3.46; 95% CI: 2.24-5.33; P < 0.00001). Security analysis revealed that the incidence of immune-mediated adverse events (imAEs) (HR: 3.77; 95% CI: 1.99-7.15, P < 0.0001) and grade 3/4 imAEs (HR: 7.01; 95% CI: 2.48-19.81; P = 0.0002) increased significantly with ICI plus chemotherapy.ConclusionsICI combined with chemotherapy as first-line treatment can significantly improve the OS and progression-free survival (PFS) of ES-SCLC patients, but the toxicity caused by immunotherapy should be carefully considered.Key pointsSignificant findings of the studyOur meta-analysis shows that PD-L1/PD-1 plus chemotherapy can significantly improve the OS and PFS of ES-SCLC patients when used as first-line therapy.What this study addsThis study fills gaps regarding the efficacy of immunotherapy combined with chemotherapy as first-line treatment for ES-SCLC, and provides better evidence for the use of PD-L1/PD-1 immunotherapy plus chemotherapy for patients with ES-SCLC.

Dataset Information

PD-1/PD-L1 Inhibitors plus Chemotherapy Versus Chemotherapy Alone for Resectable Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Publications

PD-1/PD-L1 Inhibitors plus Chemotherapy Versus Chemotherapy Alone for Resectable Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

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